Efficiency of transcranial electrostimulation on anxiety and insomnia symptoms during a washout period in depressed patients. A double-blind study

In order to test the efficacy of cerebral electrostimulation (electrosleep) as an alternative to drug therapy for the treatment of anxiety and insomnia, we conducted a double-blind study in a sample of 21 depressed inpatients submitted to a 5-day period of drug washout on admission to the psychiatric department. During this withdrawal period, anxiety and insomnia were exacerbated in the placebo group, whereas anxiety decreased and sleep duration improved in the active treatment group, with a divergent evolution during the 5-day washout period. The depressive criteria did not respond differentially to treatment, however. Thus, the effects of this drug washout period are markedly attenuated by cerebral electrostimulation, which is of possible interest in the management of psychotropic drug withdrawal.     

A comparison of placebo responders and nonresponders in subgroups of depressive disorder.

The objective of this study was to determine if the placebo treatment response varied in subgroups of depressed patients (single episode, recurrent, and double depression). Data from placebo-treated patients from seven placebo-controlled clinical trials were pooled and analyzed retrospectively. The placebo response rate was highest for females with a single episode of depression (66.7%) and lowest for females with recurrent depressive episodes (13.3%). Among patients experiencing their first episode, placebo responders had lower Hamilton Rating Scale for Depression (HAMD) total scores at baseline and lower ratings of pschomotor retardation than nonresponders. For patients having a recurrence of an episode, placebo responders had lower baseline ratings of somatic anxiety. The major finding was that patients suffering from their first depressive episode differed from patients with recurrent depressive episodes in the rate of placebo response, effect of gender, and the clinical symptoms that were associated with a positive placebo response.     

A controlled study of intravenous immunoglobulin in demyelinating neuropathy with IgM gammopathy

Eleven patients with demyelinating polyneuropathy associated with monoclonal IgM antibodies were randomized to receive IVIg or placebo, monthly, for 3 months in a double-blind study. After a washout period, they crossed over to the alternate therapy. Response was gauged by evaluating muscle strength, sensation, and neuromuscular symptoms at baseline, after 3 months, and at treatment's end. After IVIg therapy, the strenght improved in only 2 of 11 patients, by 28 and 38.5 points from baseline, and declined after placebo. In 1 other patient, the sensory score improved by 13 points. Antibody titers to MAG/SGPG or gangliosides did not appreciably change. We conclude that IVIg has only a modest benefit to not more than 18% of patients with IgM paraproteinemic demyelinating neuropathy.     

Antecedent life events,social supports and response to antidepressants in depressed patients

We evaluated 355 subjects who entered one of six double-blind placebo-controlled antidepressant drug trials with respect to the occurrence of antecedent adverse life events and their meaning to the patient. Patients were also assessed with regard to the degree of social support they received for the negative life event. The groups differed as to whether they did or did not meet the criteria for melancholic depression; 43 one-week placebo responders were statistically significantly more likely to believe that adverse life events predisposed them to depressive illness and that such life events precipitated their current depression, compared to 312 one-week placebo non-responders. Of the 312 patients who went on to the double-blind phase in which they were treated with either drug (n= 204) or placebo (n= 108), it was noted that, for both melancholic and non-melancholic patients, responders to drug treatment (but not placebo) had a more favourable ratio of social support received/social support desired than non-responders. Non. melancholic responders to both drug and placebo were statistically significantly more likely to report fewer adverse life events and have a less strong belief that adverse life events predispose one to depressive illness than non-responders. Melancholic patients did not show this trend.     

Efficacy of gamma-hydroxybutyrate versus placebo in treating narcolepsy-cataplexy: double-blind subjective measures

The efficacy of gamma-hydroxybutyrate (GHB) versus placebo for treating narcolepsy was evaluated in 20 patients with narcolepsy, 10 men and 10 women, using a double-blind counterbalanced crossover design. Each patient completed a daily sleep-wake log and questionnaire during a 14-day baseline, a 29-day placebo period, a 29-day GHB period (50 mg GHB/kg/night given 25 mg/kg h.s. and 25 mg/kg 3 hr later), and a 6-day washout period after each treatment. Cataplexy frequency was significantly lower during GHB treatment than during placebo treatment (p = 0.022). Compared to baseline values, the number of cataplexy attacks per day declined by 52% and 69% during GHB treatment weeks 1 and 4, respectively. The number of subjective arousals from sleep was less with GHB than with placebo (p = 0.035), and the number of sleep attacks was not significantly different during GHB versus placebo treatment. GHB did not have a significant effect on subjective estimates of sleep onset latency, total sleep time, Stanford Sleepiness Scale ratings at morning wake-up, methylphenidate usage, or the number of naps per day. The results indicate that GHB is efficacious for reducing the frequency of cataplexy attacks and subjective nocturnal arousals in patients with narcolepsy within the first 4 weeks of treatment.     

Treatment of erectile dysfunction in men with depressive symptoms: results of a placebo-controlled trial with sildenafil citrate

OBJECTIVE: Depressed men commonly have erectile dysfunction, and men with erectile dysfunction are frequently depressed. Since the etiologic and modulatory relationships between depression and erectile dysfunction have been poorly characterized, a 12-week, randomized, double-blind, placebo-controlled trial was conducted at 20 urologic clinics to evaluate the effects of sildenafil treatment in men with erectile dysfunction and mild-to-moderate comorbid depressive illness. METHOD: Men (N=152, mean age=56 years) with erectile dysfunction for > or =6 months (mean=5.7 years), a DSM-IV diagnosis of depressive disorder not otherwise specified, and a Hamilton Depression Rating Scale score > or =12 (mean at baseline=16.9) were randomly assigned to flexible-dose treatment with sildenafil citrate or matching placebo. Interviewer-rated and self-report instruments were used to assess changes in sexual function, depressive symptoms, and quality of life. Conservative criteria were used to classify erectile dysfunction treatment response and nonresponse. RESULTS: Sildenafil was strongly associated with erectile dysfunction treatment response. Fifty-eight men met the conservative criteria for response (48 given sildenafil, 10 given placebo), and 78 men did not respond (18 given sildenafil, 60 given placebo). Mean decreases of 10.6 and 2.3 in Hamilton depression scale scores were seen in treatment responders and nonresponders, respectively; 76% of treatment responders showed a > or =50% decline in Hamilton depression scale score versus 14% of nonresponders. Quality of life was similarly improved in treatment responders. CONCLUSIONS: Sildenafil is efficacious for erectile dysfunction in men with mild-to-moderate depressive illness. Improvement of erectile dysfunction is associated with marked improvement in depressive symptoms and quality of life.     

Clinical predictors of response to lamotrigine and gabapentin monotherapy in refractory affective disorders.

BACKGROUND: The objective of the current study was to examine possible clinical predictors of positive response to lamotrigine or gabapentin monotherapy in treatment-refractory affectively ill patients. METHODS: Forty-five patients with treatment refractory bipolar (n = 35) or unipolar (n = 10) affective disorder participated in a clinical study evaluating six weeks of treatment with lamotrigine, gabapentin, or placebo monotherapy given in a double-blind, randomized fashion with two subsequent cross-overs to the other agents. Patients received daily mood ratings and weekly cross-sectional scales. Much or very much improved on the Clinical Global Impression scale modified for bipolar illness was considered a positive response. Degree of response was correlated with a number of baseline demographic and course of illness variables in a univariate analysis and then by linear regression. RESULTS: Response rates to lamotrigine (51%) exceeded those to gabapentin (28%) and placebo (21%). A positive response to lamotrigine monotherapy was associated with a bipolar diagnosis; fewer hospitalizations; fewer prior medication trials; and male gender (of which the latter two variables survived logistic regression). For gabapentin, degree of response correlated with shorter duration of illness; younger age; and lower baseline weight (with the latter two surviving linear regression). CONCLUSIONS: In this highly treatment-refractory population, lamotrigine appeared most effective for male patients with fewer prior medication trials. Gabapentin monotherapy, although not better than placebo, appeared most effective in those with younger age and lower baseline weight. These preliminary data in a treatment refractory subgroup may help in the further definition of the range of clinical utility of these widely used anticonvulsants.     

Clinical features of depressed patients who do and do not improve with placebo.

The substantial placebo response in depression confounds treatment decisions and the assessment of new therapies. Improvement with placebo occurs infrequently in patients with chronic depression and in those with pituitary-adrenocortical hyperfunction, but other consistent predictors of placebo response have not been detected. We divided 241 moderately to severely depressed patients who had received placebo on a double-blind basis for 3 to 6 weeks into responders (greater than or equal to 50% improvement in Hamilton depression score, final Hamilton depression score less than or equal to 10), extreme nonresponders (less than 25% improvement), and partial responders (all others). Improvement with placebo was associated with a relatively short illness, a precipitating event, depression of only moderate global severity, and a good response to previous antidepressant treatment. These observations suggest that depressed patients who do and do not recover with placebo have different conditions that have not yet been fully characterized.     

Gepirone extended-release: new evidence for efficacy in the treatment of major depressive disorder

OBJECTIVE: To assess the efficacy and tolerability of the 5-HT(1A) agonist gepirone in extended-release formulation (gepirone-ER) versus placebo in patients with major depressive disorder. METHOD: Patients aged 18 to 70 years were eligible if they satisfied DSM-IV criteria for moderate-to-severe major depressive disorder and had a baseline 17-item Hamilton Rating Scale for Depression (HAM-D-17) score > or = 20. After a 4- to 7-day placebo washout period, patients were randomly assigned to receive either placebo (N = 106) or gepirone-ER (20-80 mg/day) (N = 103) for 56 days. Assessments were done at weeks 1-4, 6, and 8. RESULTS: Mean change from baseline in HAM-D-17 score within the intent-to-treat group (gepirone, N = 101; placebo, N = 103) was significantly greater with gepirone-ER than placebo at weeks 3 (p =.013) and 8 (p =.018). Significantly (p <.05) more patients receiving gepirone-ER than placebo were HAM-D-17 responders at weeks 3 (33.7% vs. 18.8%, respectively) and 4 (38.6% vs. 24.8%, respectively) and HAM-D-17 remitters at weeks 6 (24.8% vs. 13.9%, respectively) and 8 (28.7% vs. 14.9%, respectively). Mean change from baseline for HAM-D-25 total score was significantly (p < pr =.05) greater with gepirone-ER at all assessments except week 6. The proportion of HAM-D-25 responders was significantly greater (p < or =.05) with gepirone-ER at weeks 3 and 8. Gepirone-ER was well tolerated: 9.8% of the gepirone-ER group and 2.8% of the placebo group discontinued due to adverse events. Common adverse events were considered mild and included dizziness, nausea, and insomnia. Gepirone-ER did not differ statistically compared with placebo in weight gain or sedation. Furthermore, preliminary evidence suggested that gepirone-ER may not be associated with sexual dysfunction. No serious adverse events occurred in gepirone-treated patients. CONCLUSION: Gepirone-ER is effective for the short-term treatment of major depressive disorder and is well tolerated.     

Correlates of therapeutic response in panic disorder presenting with palpitations: heart rate variability, sleep, and placebo effect.

OBJECTIVE: To examine the correlates of therapeutic response of patients with panic disorder presenting with palpitations, we hypothesized that therapeutic response would correlate with heart rate variability (HRV) and sleep measures. METHODS: After a 1-week placebo washout, 27 patients free of structural heart disease and not on cardioactive drugs were randomized in a double-blinded fashion to 4 weeks of treatment with clonazepam (a known antipanic agent) or placebo. We performed standard sleep measures and recorded HRV from 24-hour Holter acquisitions at baseline and end of study. We defined response to therapy as a 50% improvement in the Hamilton Anxiety Rating Scale (HARS) score, confirmed by questionnaires and reaction to sodium lactate infusion. RESULTS: There were 12 responders and 15 nonresponders. Normalization of sleep pattern (including less stage 1 and rapid eye movement [REM] sleep) was observed in both drug and placebo responders (P = 0.011 and P = 0.05, respectively) and in placebo responders alone, compared with nonresponders (P = 0.006 and P = 0.013, respectively). Placebo responders were more likely to show less depression, but even after we controlled for depression, main sleep effects remained. None of the HRV measures correlated with response, but compared with placebo, clonazepam led to a decrease in all the time and frequency domain measures of HRV (all P < 0.05). CONCLUSIONS: Central mechanisms are related to the therapeutic response of patients with panic disorder presenting with palpitations, but this does not directly correlate with HRV. Larger and longer studies may allow objective explanations of placebo response in panic disorder.     

Thyroid functioning during treatment for depression.

Thirty-nine unipolar depressed patients were treated, after a washout period of seven days in a double blind study with either moclobemide, placebo or amitriptyline, for 42 days. The psychopathological assessment and HRSD were done on seven day intervals and thyroid analysis was done on 14 day intervals. At the end of therapy, the levels of T4 and fT4 decreased significantly in the responders if amitriptyline was used, and non-significantly if placebo or moclobemide were used. The T4 and fT4 values of the non-responders increased non-significantly. The weight change was minimal and non-significant.     

Effects of pill-giving on maintenance of placebo response in patients with chronic mild depression

Fifty outpatients with mild, chronic, mood-reactive depression whose mood improved markedly after a 10-day single-blind placebo trial were randomly assigned in a double-blind design either to have their placebo medication discontinued or to have it maintained for an additional 6 weeks. Half of the patients in each condition relapsed within 6 weeks, indicating that pill-taking itself does not influence maintenance of placebo response. Placebo response was more likely to be maintained in patients who were currently married. At the end of 3 months, the overall relapse rate was 58%. The authors raise questions about the utility of the initial 10-day placebo washout in antidepressant clinical trials, and they discuss limits on the generalizability of their findings.     

Mirtazapine in essential tremor: a double-blind, placebo-controlled pilot study.

We sought to determine whether mirtazapine is safe and well-tolerated as a treatment for essential tremor (ET). We studied mirtazapine in a randomized, double-blind, placebo-controlled, crossover study of 17 ET patients. Patients were started with 15 mg per day of either mirtazapine or placebo for 1 week and the dose was escalated weekly until the targeted dose of 45 mg per day was achieved. This dose was maintained for 2 weeks. Tremor was assessed at baseline and after 14 days of 45 mg of mirtazapine or placebo. There was a minimum washout period of 14 days between the two arms of the study. Tremor assessments included global improvement, Fahn Tolosa Marin Tremor Rating Scale, Beck Depression Inventory and the Parkinson's Disease Questionnaire-39. Patient global improvement ratings indicated that in the placebo condition 12 patients were unchanged and 1 patient was mildly improved. In the mirtazapine condition, 10 patients were unchanged, 2 were moderately improved and 1 was markedly improved. There was no significant improvement with mirtazapine or placebo compared to baseline as measured by the Tremor Rating Scale. Adverse effects were more common in the mirtazapine group and included drowsiness, confusion, dry mouth, weight gain, polyuria, itching, nausea, gait and balance problems, blurred vision, and bad taste. We conclude that the majority of the ET patients do not benefit from mirtazapine. Mirtazapine has significant adverse effects and should be used cautiously in ET patients.     

Systemic alpha-interferon therapy of multiple sclerosis

A randomized, double-blind, placebo-controlled crossover study tested the efficacy of natural alpha interferon in altering exacerbating-remitting MS. Twenty-four patients with frequent exacerbations were treated for 6-month periods, beginning with either 5 X 10(6) IU of interferon daily or placebo. A 6-month washout period followed each treatment. Exacerbation rates were reduced during interferon and placebo phases compared with pre-study rates; a greater reduction occurred on interferon, particularly following placebo, possibly reflecting a learning phenomenon. Fifteen patients with a strictly exacerbating-remitting course had fewer and milder exacerbations on interferon compared with those on placebo, whereas 9 patients with a progressive component continued to have active disease. These results suggest that interferon might reduce exacerbations in certain patients and indicate guidelines for future trials of interferon in MS.     

A double-blind study of alprazolam and oxazepam in the treatment of anxiety

In a randomized double-blind study with parallel group design involving 60 anxious psychoneurotic outpatients, the anxiolytic activity of alprazolam was compared with that of oxazepam. Following a 4 to 7-day placebo washout period, both groups showed a similar and significant response to treatment during the 4-week active treatment phase. An important intergroup difference emerged in the fear/anxiety component of the Lipman SRSS with the alprazolam groups showing a significantly greater mean reduction from the baseline score. During alprazolam treatment there was also a significant reduction in the depression factor score of the Lipman SRSS by the termination of the study and for all 4 weeks combined. Furthermore, the global impression of treatment was judged by patients as more favourable towards alprazolam than towards oxazepam. Only one person in each group reported a serious side effect. The results indicate that the anxiolytic activity of alprazolam is at least as good as that of oxazepam.     

A Double-Blind Study of Paroxetine, Fluoxetine, and Placebo an Outpatients with Major Depression

We report results from a multicenter, placebo-controlled, randomized, double-blind comparison of the efficacy and tolerability of paroxetine and fluoxetine in outpatients with major depression. Across five U.S. sites, 128 outpatients (mean age: 41.3 ± 12.6; 63 men and 65 women) with moderate to moderately severe major depression without a history of mania or hypomania were recruited between 1993 and 1994. All 128 patients completed a 1-week placebo washout period, and were then randomized to 12 weeks of double-blind treatment with paroxetine up to 50 mg/day (n = 55), fluoxetine up to 80 mg/day (n = 54), or placebo (n = 19). Subjects were evaluated weekly for the first 4 weeks, then at weeks 6, 9, and 12 with the 21-item HAMD and the Covi Anxiety Scale. There were no significant differences among the three treatment groups in baseline and endpoint depression and anxiety severity, as well as in the degree of depression and anxiety improvement. There were no statistically significant differences in rates or mean numbers of adverse events between paroxetine-treated patients and fluoxetine-treated patients. In summary, our results, although limited by the lack of a significant difference from placebo in treatment outcome, suggest that the SSRIs paroxetine and fluoxetine have comparable antidepressant and antianxiety efficacies among depressed outpatients, as well as similar safety and tolerability profiles.     

DHEA treatment for HIV+ patients: effects on mood, androgenic and anabolic parameters

The goal of this pilot study was to evaluate the effect of dehydroepiandrosterone (DHEA) on depressed mood and fatigue in HIV+ men and women, unselected for baseline DHEA level. Secondary questions concerned treatment effects on libido and body cell mass, on serum testosterone levels, and elicitation of short-term side effects. Treatment consisted of an open-label 8-week trial using DHEA doses from 200 to 500 mg/day. Mood responders were maintained for another 4 weeks, then randomized to a double blind placebo controlled 4-week discontinuation trial. Forty-five patients, including six women, entered the trial. Of 32 week 8 completers, mood was much improved in 72%, and 81% were rated responders with respect to fatigue. Response on either parameter was unrelated to baseline serum DHEA level. Twenty-one patients entered the double blind discontinuation phase. No differences in relapse rate between placebo and DHEA groups were observed for either mood or fatigue. Body cell mass increased significantly by week 8, and this improvement was maintained throughout the double blind phase for patients in both treatment conditions. Libido increased significantly as well. DHEA therapy did not have an effect on CD4 cell count or on serum testosterone levels in men. In conclusion, DHEA may be a promising treatment for HIV+ patients with depressed mood and fatigue, although persistence of response even in placebo-treated patients during the discontinuation phase leaves unresolved questions. A parallel group double blind clinical trial is indicated as the next step to more clearly identify therapeutic efficacy.     

Plasma MHPG in depression: Effects of acute and chronic desipramine treatment

The effects of acute and chronic desmethylimipramine (DMI) administration on 3-methoxy-4-hydroxyphenylethyleneglycol (MHPG) in plasma and urine were examined in eight depressed inpatients. DMI treatment induced an immediate and continous highly significant reduction in plasma MHPG throughout the 30-day treatment period. This effect was not related to treatment response. In contrast to plasma MHPG, there was no uniform effect of DMI treatment on urinary MHPG. Chronic DMI treatment increased or did not change urinary MHPG in the three treatment responders and decreased urinary MHPG in five nonresponders. The correlation between plasma and urinary MHPG during the placebo period was not significant, and the effect of DMI treatment on the two measures differed markedly.     

Duration of antidepressant drug treatment. What is an adequate trial?

Data from three six-week placebo-controlled randomized antidepressant trials were pooled to test the hypothesis that a four-week trial is insufficient to reach a determination of drug failure in depressed patients. We compared global clinical ratings at weekly intervals for patients receiving drug and patients receiving placebo and calculated the proportion of patients whose clinical status changed over time. We predicted, and found, that a significant proportion of patients who showed no clear-cut response at four weeks would show much improvement at six weeks in drug but not placebo conditions. Baseline Research Diagnostic Criteria diagnosis, baseline illness severity, and drug dose adjustments after four weeks did not predict either late clinical improvement or relapse between four and six weeks. Additional placebo-controlled studies are needed to replicate our findings concerning the advantage of extending trials to five or six weeks in samples of patients of various depressive subtypes.     

Open, Double-Blind and Long-Term Study of Vigabatrin in Chronic Epilepsy

We performed an open, double-blind, and long-term study of vigabatrin (gamma-vinyl-GABA, GVG) in patients with treatment-resistant epilepsy who were receiving only one or at most two standard antiepileptic drugs (AEDs). The novel design included a parallel, double-blind, placebo-controlled phase that minimized the number of patients receiving placebo and allowed determination of the optimum dose of GVG for each patient before initiation of the double-blind phase. The study was divided into four phases. The first phase was a 6-week period of baseline observation. In the second phase, GVG was added openly to previous AEDs for 8 weeks. During the first 2 weeks of this phase, the dose of GVG was increased weekly and then, in the absence of adverse effects, was held constant for the next 6 weeks. At the end of this open phase, seizure frequency during the 6 weeks of constant treatment was compared with the baseline seizure frequency for each patient. Patients who experienced reduction greater than 50% in the frequency of any seizure type during the open phase were defined as responders. These responders were then entered into the third and double-blind phase, in which they were randomly allocated wither to continue active GVG treatment or placebo for 8 weeks. Thirty-three patients entered the study; 31 of 33 patients completed the initial open phase. Twenty patients achieved a reduction greater than or equal to 50% in the frequency of one or more seizure types and were eligible for the double-blind phase; 10 were randomized to continue GVG and 10 were randomized to placebo.(ABSTRACT TRUNCATED AT 250 WORDS)